Cyclophosphamide is the generic name for 2-[bis(2-chloroethyl)amino]-tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide monohydrate, a widely used antineoplastic drug chemically related to the nitrogen mustards. Cyclophosphamide is one example of a group of cyclic phosphoric acid ester amides which were disclosed and claimed in U.S. Pat. No. 3,018,302 granted Jan. 23, 1962 to H. Arnold et al. Cyclophosphamide is sold under the proprietary name CYTOXAN. ENDOXAN and NEOSAR are other proprietary names for similar pharmaceutical formulations of cyclophosphamide. The commercial cyclophosphamide product is a sterile dry mixture of cyclophosphamide monohydrate.
While the crystal form of cyclophosphamide used in these products is the monohydrate, which is the easiest to isolate and with which to work, the anhydrous form also exists. As used herein, the term “cyclophosphamide” refers generically to the drug substance regardless of the crystal form, the term “cyclophosphamide monohydrate” refers specifically to the monohydrate and the term “anhydrous cyclophosphamide” refers to the anhydrous form. The monohydrate form is preferred for pharmaceutical processing, since the anhydrous form readily picks up water to form the monohydrate when exposed to a relative humidity of about 20-30% or higher at about 25° C. While the monohydrate is stable, nonetheless, under dry conditions (e.g. a relative humidity of about 20% or less) the monohydrate begins to lose this water of hydration which can reduce stability during manufacturing. Because of stability limitations which may be due in part to ready inter-conversion between the anhydrous and monohydrate forms, it is recommended that storage temperatures for cyclophosphamide products not exceed 30° C. (86° F.), and preferably be stored at or below about 25° C. (77° F.).
Currently, the parenteral dosage formulations of cyclophosphamide consist of sterile packaged dry powder fill of cyclophosphamide monohydrate. The sterile powder is dissolved in water or normal saline prior to administration, which can be oral as well as parenteral. It is intended that the solution itself be administered promptly after being prepared but it is satisfactory for use up to several hours after preparation. During processing and/or storage of the currently available dry powder formulation, the product can acquire a glassy and/or sticky nature resulting in an undesirable material with prolonged dissolution times and decreased potency. This deterioration is more pronounced as storage time is extended or if the upper limit of the storage temperature range is exceeded.
A common practice used with constitution of sterile solids by a suitable aqueous vehicle consists of warming the solution in the container to expedite the dissolution process, especially when the solids dissolve slowly. A study examining the effect of briefly heating cyclophosphamide solutions was reported by D. Brooke, et al. in American Journal of Hospital Pharmacy, 32:44-45 (1975). This study concluded that warming vials of cyclophosphamide in order to facilitate dissolution after adding an aqueous vehicle could decrease the potency of the final injectable product. In summary, these stability limitations and dissolution difficulties can often result in clinical usage of sub-potent cyclophosphamide solutions.